Acylated p-aminobenzene sulfonamides



Patented Dec. 28, 194

ACYLATED p AMINOBENZENE SULFONAMIDE S Rudolf Hirt, Riehen, and HansGysin and Henry Martin, Basel, Switzerland, assignors to J. R. Geigy A.G., Basel switzerland, a Swiss firm No Drawing. Application March 10,1945, Serial No. 582,182. In Switzerland November 5, 1943 It has beenfound that especially valuable acyl ated p-aminobenzene sulfonamides ofthe general formula wherein R1 and R2 mean hydrogen, the same ordifferent alkyl, cycloalkyl, aralkyl or aryl radicals,

R3 means alkyl, cycloalkyl, aralkyl, aryl or heterocyclic radicals,

R4 means hydrogen, alkyl or aralkyl radicals,

R5 means hydrogen or an alkyl radical and Z means S or O,

are obtained, when sulfonamides of the benzene series containing inp-position to the sulfonamide group a nitrogen-containing group which,if desired, is convertible into the amino group are caused to react withcarboxylic acids of the general formula R1 nooo-t i-z-ra wherein R1 toR3 and Z have the above-mentioned meanings, or with their functionalderivatives and when, if desired, the p-positioned nitrogen-containinggroup is converted into a free amino group or into an amino groupsubstituted in a desired manner. Compounds of this kind have not becomeknown heretofore; the same differ from the known acylated p-aminobenzenesulfonamides by their improved efficacy against infection promoters andb their lower toxicity.

As sulfonamides of the benzene series containing a nitrogen-containinggroup in p-posltion to the sulfonamide group may be mentioned p--'sulfonamide, alkyl-, aralkyloff by a hydrolytical treatment withoutchanging the acylated sulfonamide group by this procedure.

The same products are also obtained by interaction of correspondinge-halogen carboxylic acid derivatives or oc-SlllfOlllC acid estercarboxylic acid derivatives with the corresponding sulfonamides Advan- 6Claims. (01. zen-397.7)

2 and by a subsequent interaction with alcohols, phenols, mercaptans ortheir salts.

A special modification of the present process leading to the sameproducts consists in that benzene sulfone halides containing a,nitrogencontaimng group in p-position are condensed with salts of amidesof the general formula 1?: RaZ-(|3C O-NHz wherein R1 to R3 and Zcorrespond to the aforesaid meanings, and that, if necessary, thep-positioned group is converted into an amino group or into anitrogen-containing group substituted in the desired manner.

As carboxylic acids of the formula lh R;, 2-0-0 0 OH may be enumeratedfor example: methoxy-,

sulfonamides, p-acylaminobem ethoxy-, propoxy-, isopropoxy-, a1lyloxy-,butoxy-, isobutoxy-, pentoxy-, hexoxy-, heptoxy-, octoxy-, nonoxy-,decoxyetc. -acetic acid, a-methoxya-ethoxy, a-propoxy-, abutoxy-,a-isobutoxy-, a-hexoxy-, u-octoxy-, a-lll'ldBCOXY- etc. -propionic acid,a-methoxy-, a-ethoxy-, a-propoxy-', a-isopropoxy-, a-butoxyetc. -butyricacid, a-methoxy-, wethoxy, a-propoXy-, a butoxyetc. -isobutyric acid,a-methoxy-, a-ethoxy, a-butoxy-, etc. -valeric acid, a-II16th0Xy,a-ethoxy-, a-propoxyetc. -isovaleric acid; moreover, correspondingcapronic, oenanthylic, caprylic acids and so on; cyclopentyloxy-,cyc1opentenyloxy-, methylcyclopentyloxw, cyclohexyloxy-,cyclohexenyloxy-, cycloheptyloxy-acetic acid etc., a-cyclopentyloxy-,a-cyclohexyloxy-propionic acid etc., a-cyclopenty1oxy-,a-cyclopentenyloxy, a-cyclohexyloxy-butyric acid etc.,cyclohexylethoxy-, (p-me thylcyclohexy1)-ethoXy-acetic acid, etc.,benzyloxy-, 4-methylbenzyloxy-, Z-methylbenzyloxy-, 3-methylbenzyloXy-,3:4-dimethylbenzyloxy-, phenethoxy-, 'y-pheny1propoxy-, cinnamyloxy-,p-methyl-cinnamy1oxy-acetic acid etc., ab,enzyloxy-, oc- (3:4-dimethylbenzyloxy) a-(b phenethoxy), a-cinnamyloxy propionic acid,furthermore, corresponding butyric, valeric acids etc.,(a-methylbenzy1oxy)-, (4m-dimethylbenzy1oxy)-acetic acid,a-(w-methylbenzyloxy) propionic acid etc., phenoxy-, 4-methylphenoXy-,3-methylphenoxy-,- .2-methylphen0Xy-. 3:4-dimethy1phenoxy-,4-amylphenoxy-, 4-metho5cyphenoxy -4-chlorophenoxy-acetic acid,u-phenoxy-, a- (4 methylphenoxy) a- (3 :4-dimethylphenoxy)-,e-(2-methoxyphenoxy) propionic acid etc., a-phenoxy-, a-(3-cresoxy)-,-thymoxy-, e-carvacroxy-, a-(4-methyl-3-methoxyphenoxy)-butyric acidetc., a-phenoxy-, a-(p- 3. cresoxy) a.-(3:4-xylenoxy)- valeric' acidetc, a-phenoxy-, a-(3-0hlOIODhi-3I1OXY) a-(2-cresoxyl-isovaleric acidetc. Corresponding derivatives of capronic, oenanthylic, caprylic acid.etc may also be used.

Phenoxy-cyclopentyl-acetic acid, m-cresoxycyclopentyl-acetic acid,phenoxy cyclohexylacetic acid etc, diphenyloxy-, tolylphenyloxy aceticacid, etc, a-naphthoxy-, c-naphthoxyacetic acid etc.,o-phenylphenoxy-acetic acid etc.,

may also be used.

Corresponding thioether acids, such as methyI- mercapto-, ethylmercaptopropyl ner-captoacetic acid etc., a-cthylmercapto,a-propylmercapto-propi-onic acid etc., a-ethylmercapto-,cisbpropylr'nercaptm, a-butyl-mercaptm, oc-DGHtYlmercapto-butyric acidetc, analogous isobutyric, valeric, isovaleric, capronic, oenanthyliccapyrlic acids etc, cyclopentylmercapto-, cyclopentenylmer-capto-aceticacid and other corresponding mercapto acids, as defined above as etheracids, may be used. Araliphatic acids: benzylmercapto-,fl-phenethylmercapto-acetic acid, corresponding propionic-, butyricacids etc. Among the aromatic acids which may be employed may be citedfor instance: phenmercapto-, 4-methy1- phenmercapto-acetic acid etc.Heterocyclic acids which may be employed are for example furfuryloxy-,2'-pyridinoxy-, 6'-quinolinoxy-, I-cumarinoxy-, 2-quinoxalinoxy-aceticacid etc,, c-furfu'ryloxy-, a-(2'-pyridinoxy) ui3f-pyridinoxy)-, a-(4-pyridinoXy) -propionic acid etc. Besides substituted aliphatic oxyacids may-be used, e. g. cyc1opentyl-methoXy-, cyclohexyl ethoxy aceticacid, methoxy-dicyclopentenyl-acetic acid, methoXy-cinnamyl-,propoxy-benzyl-acetic acid etc., methoxy-pheny1-, ethoxy-tolyl-aceticacid, then the corresponding propionicbutyric acids etc.

The acids mentioned above are partly known;

where this is-not thecase, the same can be pre pared according to knownmethods.

The acids can be used as such for instance in the presence of catalystsor in form of their functional derivatives; besides it is also possible.to concomitantly use acid binding or condensing agents.

As nitrogen-containing group may be ,enumerated the nitro, amino,acylamino, ureido, urethano, aminoalkylene sulfonic acid,- alkylamino oraralkyl-amino group and the like.

The present invention will now :be illustrated, but no limited, by thefollowing examples, the par-ts being by weight.

Example 1 30 parts of a-ethoxybutyric acid chloride are dissolved in 100parts of pyridine with coolingand stirring. Then 40 parts ofp-nitrobenzene sulfonamide are added by portion and the whole is stirredfor some time at 60-'? C. Then the mixture is poured onto ice andhydrochloric acid and the resin being thus separated is isolated. Theni-tro body is reduced according to Bchamp'by means of iron andhydrochloric acid without a further purification. The reduction mixtureis subsequently made alkaline with sodium carbonate, filtered by suctionand the 4-aminobenzene sulfone-(a'-ethoxybutyroyl)- amide of the formulais precipitated from the filtrate by means of acetic acid. 13yrecrystallization from alcoholthe. com- 4 pound is obtained in pureform. Melting point 130 C.

In a completely analogous manner the following compounds may beproduced:

4-,aminoben2ene SUIfOIlB-(a' butoxypropionyhamide, M. P. 148 C.

4 ,aminobenzene sulfone (oz' isobutoxypropionyl) -amide, M. P. 146 C.

4-aminobenzene sulfone-(a' butoxybutyroyD- amide, M. P. 105 C.

4-aminobenzene sulfone- (a' -isobu-toxybutyroyl) amide, M. P. 130 C.

kaminobenzene sulfone-(a' methoxyisobutyroyl) -amide, M. P. 158 C.

,4 -;aminob enzene sulfone (11 -ethoxyiSOb ll I0yl) amide, M. P. 138 C.

4-aminobenzene SlllfOl'iB-(a' propoxyis-obutyroyl) -amide, M. P. 135-136C.

4-aminobenbene sulfone- (methoxyacetyl) -amide,

lVLP. 210C.

4-aminobenzene sulfone-(ethoxyacetyl) amide,

4 aminobenzene sulfone (isopropoxyaiietybamide, M. P. 17 0 C.

4-aminobenzene sulfone- (propoxyacetyl) amide,

M. P.'124 C.

4 aminobenzene sulfcne (isobutoxy-acetyD- amide, M. P. 137 C.

4-aminobenzene sulfone-(a' ethoxypropionyD- amide M. P. 130 C.

4-aminobenzene sulfone (w-propoxypropionyl) amide, M. P. 140 C.

larninobenzene sulfone (a' -isopropcxypropionyl) -amide, M. P. 150 C.

l-aminobenzene sulfone-(e' propoxybutyroybamide, M. P. 118C.

Example 2 30 parts of p-nitrobenzene sulf-onamide are suspended in 100parts of chlorobenzene, then 16 parts of a-propylmercaptopropionie acidchloride are dropped thereto and the mixture is boiled under reflux forsome hours. After complete reaction the chlorobenzene is distilled withsteam, the residue isdissolvedin a sodiumcarbonate solution, treatedwith animal charcoal, filteredand the {l-nitrobenzenesulfone-(a-propylmercapt0- propionyl) -amide is precipitated from thefiltrate by'means of hydrochloric acid. By reduction the nitro bodygives the corresponding amine ,of the formula QaH'l-S-CH-O o-NH-smONmwhich, when recrystallised from alcohol, meltsat 158 C.

In an analogous manner may be obtained:

;4-amin obenzene sulfone- (ethylmercaptoacetyl) amide, M. P. l76-l78 c.

41 aminobenzene sulfone (propylmercapt-o acetyl) -ar nide, M. P. 168 .C.

Emample 3 'the solution treated with animal charcoal, filtered and thefiltrate is acidified by means of hydrochloric 'aci-d. By saponificationof this solution with caustic soda lye the 4-aminobenzene sulfone-(cyclopentyloxyacetyl) -amide of the formula is easily obtained.

In an analogous manner may be produced the 4-aminobenzene sulfone-(cyclohexoxypropionyl) amide, melting at 170 C.

' Example 4 6 -3114: 0 mil-segue on: CHa

is obtained, which is purified by recrystallisation from alcohol.

According to the same method or according to the process described inthe Examples 1 to 3 the following compounds can be made:

4 aminobenzene amide, M.-P. 140 C.

4-.a'ininobenzene sulfone-(4' methylphenoxyacetyl) -amide, M. P. 148 C.

sulfone (ph-enoxyacetyl) 4-aminobenzene sulfone (2 methylphenoxyacetyl)amide, M. P. 218C.

4-aminobenzene sulfone (3 methylphenoxyacetyl) -arnide, M. P. 180 C.

4-aminobenzene su1f'one-(2:5' dimethylphenoXyacetyD-amide, M. P. 205 C."4 aminobenzene sulfone (4' ethylphenoxyacetyl) -amide, M. P. 155 C.

4-aminobenzene sulfone- (2 -isopropyl-5 -methy1- phenoXy-acetyl) -amide,M. P. 192 C. p

4.- aminobenzene sulfone (4 butylphenoxyacetyD-amlde, M, P. 128130 C.

4-aminobenzene sulfone-(4' isoamylph-enoxyacetyl) -amide, M. P. 194 C.

4 aminobenzene sulfone (4' hexylphenoxyacetyl) --amide, M. P. 125-126 C.

4 aminobenzene sulfone (4' chlorophenoxyacetyl) -amide, M. P. 185186 C,

4-aminobenzene sulfon-e (4-tertiary butylphenoxyacetyl) -amide, M. P.193194 C 4 -amlnobenzene sulfone (B naphthyloxyacetyl) -amide, M. P. 207C.

4-aminobenzene sulfone- (a-naphthyloxy-acetyl) amide, M. P. 245 C. r

4-aminobenzene sulfone- (4' -phenethylphenoxyacetyl) -amide, M. P. 180C.

4-aminobenzene sulfone-(4' isobutylphenoxyacetyl) -amlde, M. P. 140 C.

4 aminobenzene sulfone (phenylmercaptoacetyl) -amide, M. P. 149 C.

4-aminobenzene su1fone-(4' methylphenylmercaptoacetyl) -amide, M. P. 166C.

4-aminobenzen sulfone-(4 chloroph-enylmercaptoacetyD-amide, M. P.141-142 C.

4 aminobenzene sulfone (2' methoxy 4- chlorophenylmercaptoacetyl) amide,M, P. 144-145 C.

4 aminobenzene sulfone (3'14 dimethyl phenylmercaptobutyroyl) amide, M.P. 223-225 C.

4 -aminobenzene sulfone (a' phenoxypro pionyl) amide, M. P. 148 C.

4 aminobenzene sulfone (a' phenoxyisobutyroyl) -amide, M. P. 182 C.

4 aminobenzene sulfone (a' phenoxyvaleroyl) -'amide, M. P. 158 C.

4-aminobenzene SUIfOIIC-(oc' phenoxycaproyD- amide, M. P. C. v

4 .aminobenzene sulfone (a' phenoxyiso caproyD-amide, M. P, 127-130 C.

4 aminobenzene sulfone (oc' 3:5'-dimethylphenoxyisovaleroyl)-amide, M.P. 133134 C.

4 aminobenzene sulfone (a phenoxyisovaleroyl) -amide, M. P. 181 C.

Ercample 5 In a round bottom-ed flask 36 parts of 4-nitrobenzene sulfonechloracetamide are dissolved in the calculated quantity of dilutecaustic soda lye. Then at room temperature .a solution of 23 parts of4-chloro-2-methoxybenzylmercaptan in caustic soda lye is added thereto,whereby the temperature rises to 30-35 C. The mixture isstirred for'somehours at this temperature, filtered by suction and, from the filtrate,the nitro body is precipitated by means of hydrochloric acid. Whenrecrystallised from dilute alcohol, the nitro body melts at C. Byreduction with iron and hydrochloric acid the 4-aminobenzenesulfone-(4-chloro-2 methoxybenzylmercaptoacetyl) amide of the formulaQoms-om-c O-NH-SOz-ONH;

The reaction scheme for the aforedescribed reaction may be representedas follows:

NmOsw-NH-m-om-m PIS-CHOW (Prepared from p-nitrobenzene sulfonamide andchloroacetic acid chloride) l (Reduction) 0 CH;

NHI-OSOr-NH-O 0-CH2-S-GH2-O o COH;

I'nsteador 4 -nitrobenbene sulfone chloracetwherein'Ri'andiRaaeachrepresentsa lowert'allwl amide, the analogouscompound-containing theradical and-R2 represents a membereseleeted from sulfomethyligroup,instead)oftthes-chlorine atom the group consisting of hydrogen anda.lower can be used. I alkyl'i'a'dical.

' In-.-an.-analogous-manner may be prepared: 5 2. An acylated'p-aminobenzen'e sulfonamid of 4 aminobenzene sulfonei- (4"methoxybenzylthe formula mercaptoacetyD-amide, P; 110 r l-aminobenzenesulfone (2-methoxy-5'schloro- W wherein R represents a lower alkylradical.

y pto y de,M;P.144C. 3. The acylated; p aminobenzene sulfonamide Example6 Q I f t e formula" 22.4-parts f the 8011111111 salt ofpnitrob'e'n'zene CH CH CH O cH C Q NH SQ2O' NH2 sulfonamide are-suspendedin 150 parts of nitr0 V 1 benzene and treated with 22 parts' of8'-quin0- 3 lyloxyacetyl chloride, the temperature rising thus 4; Theacyl'atedi po 'e ene shflfona e to C. Now, the whole is heated for someof the formula hours to 50-60- C. Then the mixtureis-intro- CH3 ducedunder stirring into a dilute sodium game--20 nate solution; the smallquantities of unchanged v r sulfonamide are filtered'ofi'wand, from thefiltrate, 0E3 v the 4 'm.tmbenzene sulfone- (8-quinoly1oxyaceto) 5. Ahacylated-p-aminoben'zene sulfonamideof aimide is precipitated with acid.By reduction 2.0- the fOTmulw "cording to Bchamp the correspondingaminoiiitlai CH3 wherein R1 represents a. loweralkyl radical. A "'3 6.The aeylated p-aminobenzene sulfonamide of the formula is'obtained, thesame being purified-by recrystal- CH3 lisati'on. (1: A

Example-7': ti- -CHr-CHrO- CONH-SO-NH, 24.4 parts of4-carbethoxyaminobenzene sillv y 7 I fonamide in,ch1orobenzene aretreated with 222.5 RUDO'LF. HIRT. parts of a-.cinnamy1ovypropionylchloride and l HANS'GYSIN. with z arts of copper-powder and-thamixtureis I I-IENRY"MARTIN. heated to boiling, for some hours. Then the I Hchlorobenzeneis distilled off with steam, theresi REFERENCES-MED duedissolved in a sodium carbonaite's i The following references areofrecord. in the filtered and the filtrate is treated with-hydrofil ofthispatent; chloric acid. The carbethoxy compound-is saponified. withdilute caustic soda lyeand there- 4 UNITED STATES PATENTS sultihg 4aminobenzene sulfone 11 cinnamyl- Number Name. Date oxypropionyl) -amideof the formula 2,289,029 Mietzsch'et a1 July'7, 1942 O 020N135 2,408,066flentrioh .et a1 Sept. 291, 1946 H3 I s FOREIGN PATENTS purified byreerystallisation from-alcohol. Number 9? Date Of course, all the acidsand their radicals emi- "111,230 A merated inthe introductory, partofthis specifi- 533,322 Great'Brltam 1941 cationcan be introduced into thesulfamide mole- OTHER REFERENCES cules according to the methodsillustrated in the above examples 1 Chemical Reviews, August, 1940,pages'113, 114,

What we claim is: -1 9. 1. An acylated p-aminobenzene sulfonamide of theformula

